Chenodiol

Submission based on the positive Phase 3 RESTORE study Mirum holds orphan designation for chenodiol in CTX Potential to have first and only therapy indicated for CTX in the US FOSTER CITY, Calif.--(BUSINESS WIRE)--Mirum Pharmaceuticals, Inc. (Nasdaq: MIRM) today announced the submission of a new drug application (NDA) for chenodiol for the treatment of patients in the U.S. with cerebrotendinous xanthomatosis (CTX). CTX is a rare autosomal genetic progressive disorder of cholesterol metabolism that affects many parts of the body. In CTX, a deficiency of the bile acid CDCA leads to a buildup of bile alcohols which precedes a toxic accumulation of cholestanol. Cholestanol is the key driver of symptomatic burden and disease progression, including irreversible neurologic dysfunction. If not treated, patients with CTX can experience symptoms that disrupt their lives and can progress over time, including chronic diarrhea, juvenile bilateral cataracts, tendon xanthomas, and neurologic deterioration. The submission of the NDA is based on the positive results of the Phase 3 RESTORE study which evaluated chenodiol in adult patients with CTX. The study met its primary endpoint of reduction in bile alcohols with high statistical significance (p<0.0001). The difference observed between placebo and active chenodiol at the end of the randomized double-blind withdrawal period was 20-fold. The RESTORE study also demonstrated that treatment with chenodiol significantly improved serum cholestanol. The most common adverse events were diarrhea and headache, the majority of which were mild or moderate and not considered to be treatment related. “Following the landmark RESTORE data, we are excited about the potential to have an approved treatment option that may reduce the progressive symptoms associated with this rare disease,” said Chris Peetz, chief executive officer at Mirum. “If approved, chenodiol would be the first and only medication approved to treat patients with CTX, enabling earlier diagnosis and treatment of these life-altering symptoms.” “When you have CTX, timely diagnosis and treatment can have a transformative impact on the lives of people living with this disease,” said Jean Pickford, executive director, CTX Alliance. “We were excited about the RESTORE data and are hopeful that the chenodiol submission to the FDA will result in an approval, enabling faster access to treatment and helping patients and their families earlier in their disease journey.” About the RESTORE Phase 3 Study The Phase 3 RESTORE study was a randomized withdrawal, placebo-controlled clinical trial which evaluated the safety and efficacy of chenodiol in patients with cerebrotendinous xanthomatosis (CTX). Chenodiol is administered at 250 mg three times daily in tablet format. The objective of the RESTORE study is to understand how the body responds, as measured by change in blood and urine biomarkers associated with CTX, when treated with chenodiol. The study involved a screening period (4 weeks), four treatment periods (totaling 6 months), and a follow-up phone call (30 days after last dose was administered). The four treatment periods consisted of: an 8-week open-label chenodiol period, a 4-week randomized withdrawal period (placebo or chenodiol), a second 8-week open-label chenodiol period for all patients, and a second 4-week randomized withdrawal period (alternate treatment to first withdrawal period). The primary analysis assessed change at the end of each double-blind withdrawal period. The study also included an open-label pediatric treatment group where all patients received liquid chenodiol. The study was conducted at multiple sites in the United States and Brazil. About Cerebrotendinous Xanthomatosis Cerebrotendinous xanthomatosis (CTX) is a rare, progressive and underdiagnosed disorder of cholesterol metabolism affecting many parts of the body. In people with CTX, the body is unable to break down cholesterol properly causing toxins (e.g., cholestanol and bile alcohols) to build up throughout the body over time. The disorder is inherited in an autosomal recessive genetic manner. Signs and symptoms of CTX include neonatal cholestasis (jaundice or bile flow interruption), chronic diarrhea, the development of bilateral cataracts before the age of 18, development of tendon xanthomas (fatty deposits in the tendons) during teenage years or later, and neurologic deterioration. The types, combinations and severity of symptoms can be different from person to person making diagnosis challenging and often delayed. About chenodiol tablets Chenodiol tablets is another name for chenodeoxycholic acid (CDCA). CDCA is a naturally occurring bile acid that was originally approved for the treatment of people with radiolucent stones in the gallbladder. More recently, the US Food and Drug Administration (FDA) granted chenodiol orphan drug designation for cerebrotendinous xanthomatosis (CTX). CTX is a rare progressive disorder that can affect the brain, spinal cord, tendons, eyes and arteries. Chenodiol is not yet indicated for the treatment of CTX but has received a medical necessity determination in the U.S. by the FDA. About LIVMARLI® (maralixibat) oral solution LIVMARLI® (maralixibat) oral solution is an orally administered, once-daily, ileal bile acid transporter (IBAT) inhibitor approved by the U.S. Food and Drug Administration for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) three months of age and older and for progressive familial intrahepatic cholestasis (PFIC) five years of age and older. LIVMARLI is also the only approved IBAT inhibitor approved by the European Commission for the treatment of cholestatic pruritus in patients with ALGS two months and older, and by Health Canada for the treatment of cholestatic pruritus in ALGS. For more information for U.S. residents, please visit LIVMARLI.com. LIVMARLI has received Breakthrough Therapy designation for ALGS and PFIC type 2 and orphan designation for ALGS and PFIC. To learn more about ongoing clinical trials with LIVMARLI, please visit Mirum’s clinical trials section on the company’s website. IMPORTANT SAFETY INFORMATION Limitation of Use: LIVMARLI is not for use in PFIC type 2 patients who have a severe defect in the bile salt export pump (BSEP) protein. LIVMARLI can cause side effects, including: Liver injury. Changes in certain liver tests are common in patients with Alagille syndrome and PFIC but can worsen during treatment. These changes may be a sign of liver injury. In PFIC, this can be serious or may lead to liver transplant or death. Your healthcare provider should do blood tests and physical exams before starting and during treatment to check your liver function. Tell your healthcare provider right away if you get any signs or symptoms of liver problems, including nausea or vomiting, skin or the white part of the eye turns yellow, dark or brown urine, pain on the right side of the stomach (abdomen), bloating in your stomach area, loss of appetite or bleeding or bruising more easily than normal. Stomach and intestinal (gastrointestinal) problems. LIVMARLI can cause stomach and intestinal problems, including diarrhea and stomach pain. Your healthcare provider may advise you to monitor for new or worsening stomach problems including stomach pain, diarrhea, blood in your stool or vomiting. Tell your healthcare provider right away if you have any of these symptoms more often or more severely than normal for you. A condition called Fat Soluble Vitamin (FSV) Deficiency caused by low levels of certain vitamins (vitamin A, D, E, and K) stored in body fat is common in patients with Alagille syndrome and PFIC but may worsen during treatment. Your healthcare provider should do blood tests before starting and during treatment and may monitor for bone fractures and bleeding which have been reported as common side effects. US Prescribing Information EU SmPC Canadian Product Monograph About Mirum Pharmaceuticals, Inc. Mirum Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to transforming the treatment of rare diseases affecting children and adults. Mirum has three approved medications: LIVMARLI® (maralixibat) oral solution, CHOLBAM® (cholic acid) capsules, and CHENODAL® (chenodiol) tablets. LIVMARLI, an IBAT inhibitor, is approved for the treatment of two rare liver diseases affecting children and adults. It is approved for the treatment of cholestatic pruritus in patients with Alagille syndrome in the U.S. (three months and older), in Europe (two months and older), and in other regions globally. It is also approved in the U.S. in cholestatic pruritus in PFIC patients five years of age and older. CHOLBAM is FDA-approved for the treatment of bile acid synthesis disorders due to single enzyme deficiencies and adjunctive treatment of peroxisomal disorders in patients who show signs or symptoms or liver disease. CHENODAL has received medical necessity recognition by the FDA to treat patients with cerebrotendinous xanthomatosis (CTX). Mirum’s late-stage pipeline includes two investigational treatments for debilitating liver diseases. Volixibat, an IBAT inhibitor, is being evaluated in two potentially registrational studies including the Phase 2b VISTAS study for primary sclerosing cholangitis and Phase 2b VANTAGE study for primary biliary cholangitis. Lastly, CHENODAL, has been evaluated in a Phase 3 clinical study, RESTORE, to treat patients with CTX, with positive topline results reported in 2023. To learn more about Mirum, visit mirumpharma.com and follow Mirum on Facebook, LinkedIn, Instagram and Twitter (X). Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include statements regarding, among other things, the potential benefits of Chenodiol tablets for patients with CTX, the success of any planned regulatory submissions relating to CTX and, if approved, the real world impact of Chenodiol versus the results seen in the RESTORE clinical trial. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as “will,” “could,” “would,” “potential” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Mirum’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks and uncertainties associated with Mirum’s business in general, the impact of the COVID-19 pandemic, and the other risks described in Mirum’s filings with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management’s assumptions and estimates as of such date. Mirum undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law. A further description of risks and uncertainties can be found in Mirum’s Annual Report on Form 10-K for the fiscal year ended December 31, 2023 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors,” as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at .

- VANTAGE PBC interim analysis shows 3.8 point reduction from baseline and 2.3 point placebo-adjusted (p=0.0026) reduction in primary endpoint of pruritus - VISTAS PSC interim analysis exceeds efficacy threshold for study continuation - Mirum to host conference call to discuss analyses, today, June 17 at 8:30 a.m. ET/5:30 a.m. PT FOSTER CITY, Calif.--(BUSINESS WIRE)--Mirum Pharmaceuticals, Inc. (Nasdaq: MIRM) today announced interim results from two Phase 2b studies evaluating volixibat, an oral ileal bile acid transporter (IBAT) inhibitor in patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Interim results from the VANTAGE study evaluating volixibat in patients with PBC demonstrated a statistically significant (-3.82, p<0.0001) improvement in pruritus for volixibat and a placebo-adjusted difference of -2.32 points in the primary endpoint, p=0.0026, as measured by the Adult ItchRO scale. 75% of patients on volixibat achieved a greater than 50% reduction in serum bile acids. In addition, there was a significant improvement in fatigue at week 16 with volixibat compared to placebo. No new safety signals were observed, and adverse events were similar between the 20 mg and 80 mg treatment groups. The most common adverse event was diarrhea (77%) with all cases mild to moderate, and mostly transient; one case resulted in discontinuation. Four patients experienced serious adverse events, including one in the placebo arm. There were no clinically meaningful changes in liver biomarkers. Adult ItchRO Change from Baseline Mean change in Adult ItchRO score* 20 mg (n=10) 80 mg (n=10) 20+80 mg (n=20) PBO (n=10) LSMean (SE) P-value -3.84 (0.609) <0.0001 -3.79 (0.564) <0.0001 -3.82 (0.414) <0.0001 -1.50 (0.585) 0.0149 Difference between VLX and PBO P-value -2.34 0.0090 -2.29 0.0075 -2.32 0.0026 *Adult ItchRO is a 0-10 numerical rating scale; MMRM weekly averaged worst daily itch score, assessed over weeks 17-28 of the treatment period. Based on these results, the VANTAGE PBC trial will continue with a volixibat dose of 20 mg twice daily. Concurrently, the interim analysis for the VISTAS PSC study was conducted and the independent data review committee recommended that the study continue with the selected volixibat dose of 20 mg twice daily, with no changes to the study. The criteria for continuation included safety as well as a predefined threshold for efficacy. The sponsor and investigators are blinded to the interim results and analysis. “The interim data from the VANTAGE study provide outstanding results in relation to what has been shown for treatment of pruritus in PBC,” said Joanne Quan, MD, chief medical officer at Mirum. “With both VISTAS and VANTAGE advancing to enroll their confirmatory portions, we are excited about volixibat as a potential future option to help patients overcome one of the most prevalent and burdensome symptoms of these rare liver diseases.” “The results of the interim analyses are very impressive as they confirm the potential of volixibat in targeting bile acids in PBC and PSC,” said Kris Kowdley, MD, Washington State University and an investigator for VANTAGE and VISTAS. “I look forward to seeing the final data with the goal of having additional therapies available to address the burden of disease in adult cholestasis.” “The symptomatic burden in PBC is significant and often an underappreciated aspect of this disease. Both itch and fatigue are devastating hallmarks of PBC that can significantly decrease quality of life,” said Carol Roberts, president of the PBCers Organization. “It is incredibly encouraging for PBC patients to see such promising results with volixibat.” Conference Call to Discuss Interim Analysis Mirum will be hosting a conference call to discuss the interim analyses from VISTAS and VANTAGE today, Monday, June 17 at 8:30 a.m. ET/5:30 a.m. PT. Join the call by dialing (404) 975-4839 (local/int’l) or (833) 470-1428 (toll-free) and using the access code: 205511. You may also access the webcast through Mirum’s Investor Relations website. About Volixibat Volixibat is an oral, minimally absorbed agent designed to selectively inhibit the ileal bile acid transporter (IBAT). Volixibat may offer a novel approach in the treatment of adult cholestatic diseases by blocking the recycling of bile acids, through inhibition of IBAT, thereby reducing bile acids systemically and in the liver. Phase 1 and Phase 2 studies of volixibat demonstrated on-target fecal bile acid excretion, a pharmacodynamic marker of ASBT inhibition, in addition to decreases in LDL cholesterol and increases in 7αC4 which are markers of bile acid synthesis. Volixibat has been evaluated in more than 400 individuals across multiple clinical trials. The most common adverse events reported were mild to moderate gastrointestinal events observed in the volixibat groups. Volixibat is currently being evaluated in Phase 2b studies for primary sclerosing cholangitis (VISTAS study), and primary biliary cholangitis (VANTAGE study). About Mirum Pharmaceuticals, Inc. Mirum Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to transforming the treatment of rare diseases affecting children and adults. Mirum has three approved medications: LIVMARLI® (maralixibat) oral solution, CHOLBAM® (cholic acid) capsules, and CHENODAL® (chenodiol) tablets. LIVMARLI, an IBAT inhibitor, is approved for the treatment of two rare liver diseases affecting children and adults. It is approved for the treatment of cholestatic pruritus in patients with Alagille syndrome in the U.S. (three months and older), in Europe (two months and older), and in other regions globally. It is also approved in the U.S. in cholestatic pruritus in PFIC patients five years of age and older and in Europe the Committee for Medicinal Products for Human Use (CHMP) has adopted positive opinion of LIVMARLI to treat patients with PFIC three months and older. A decision by the European Commission is expected in the third quarter 2024. CHOLBAM is FDA-approved for the treatment of bile acid synthesis disorders due to single enzyme deficiencies and adjunctive treatment of peroxisomal disorders in patients who show signs or symptoms or liver disease. CHENODAL has received medical necessity recognition by the FDA to treat patients with cerebrotendinous xanthomatosis (CTX). Mirum’s late-stage pipeline includes two investigational treatments for debilitating liver diseases. Volixibat, an IBAT inhibitor, is being evaluated in two potentially registrational studies including the Phase 2b VISTAS study for primary sclerosing cholangitis and Phase 2b VANTAGE study for primary biliary cholangitis. Lastly, CHENODAL has been evaluated in a Phase 3 clinical study, RESTORE, to treat patients with CTX, with positive topline results reported in 2023. To learn more about Mirum, visit mirumpharma.com and follow Mirum on Facebook, LinkedIn, Instagram and Twitter (X). LIVMARLI® (maralixibat) Oral Solution IMPORTANT SAFETY INFORMATION Limitation of Use: LIVMARLI is not for use in PFIC type 2 patients who have a severe defect in the bile salt export pump (BSEP) protein. LIVMARLI can cause side effects, including: Liver injury. Changes in certain liver tests are common in patients with Alagille syndrome and PFIC but can worsen during treatment. These changes may be a sign of liver injury. In PFIC, this can be serious or may lead to liver transplant or death. Your healthcare provider should do blood tests and physical exams before starting and during treatment to check your liver function. Tell your healthcare provider right away if you get any signs or symptoms of liver problems, including nausea or vomiting, skin or the white part of the eye turns yellow, dark or brown urine, pain on the right side of the stomach (abdomen), bloating in your stomach area, loss of appetite or bleeding or bruising more easily than normal. Stomach and intestinal (gastrointestinal) problems. LIVMARLI can cause stomach and intestinal problems, including diarrhea and stomach pain. Your healthcare provider may advise you to monitor for new or worsening stomach problems including stomach pain, diarrhea, blood in your stool or vomiting. Tell your healthcare provider right away if you have any of these symptoms more often or more severely than normal for you. A condition called Fat Soluble Vitamin (FSV) Deficiency caused by low levels of certain vitamins (vitamin A, D, E, and K) stored in body fat is common in patients with Alagille syndrome and PFIC but may worsen during treatment. Your healthcare provider should do blood tests before starting and during treatment and may monitor for bone fractures and bleeding which have been reported as common side effects. US Prescribing Information EU SmPC Forward-Looking Statements This press release contains “forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Such forward-looking statements include those regarding the clinical potential and regulatory process for volixibat, the ability for volixibat to impact bile acids or pruritus in patients with PSC or PBC, and the effectiveness of volixibat in a real-world population, if ever approved by the FDA. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as “will,” “could,” “would,” “potential” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Mirum’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks and uncertainties associated with Mirum’s business in general, the impact of the COVID-19 pandemic, and the other risks described in Mirum’s filings with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management’s assumptions and estimates as of such date. Mirum undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law. A further description of risks and uncertainties can be found in Mirum’s Annual Report on Form 10-K for the fiscal year ended December 31, 2023 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors,” as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at .